Is Treatment for Cytopenic Myelofibrosis Still an Unmet Clinical Need?

Abstract

Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of clonal hematological disorders driven by mutated hematopoietic stem cells. MF, as de novo myeloid malignancy (primary MF: PMF) or secondary to an antecedent MPN (post-ET-MF or post-PV-MF), is a life-threatening condition associated with shortened survival and risk of leukemic transformation in about 20% of the patients. 1 Clonal expansion of malignant myeloid stem-and progenitor cells and stromal changes along with increased proinflammatory cytokines production drive the remodeling of the bone marrow (BM) microenvironment and disrupt physiological hematopoiesis. Clinical manifestations of MF-associated progressive BM failure, such as cytopenia (anemia, thrombocytopenia), hepatosplenomegaly, constitutional symptoms (eg, weight loss, fever, night sweating), significantly impact patients' quality-of-life (QoL) and correlate with poor prognosis for overall survival (OS). 2,3 The identification of a constitutive JAK-STAT pathway activity and underlying somatic driver mutations in the janus kinase 2 (jak2), calreticulin (calr), and thrombopoietin receptor (mpl) genes has revolutionized the therapeutic landscape with the development of JAK inhibitors (JAKi).Ruxolitinib, a dual JAK1/JAK2 inhibitor, was the first JAKi approved for treatment in patients with intermediate-or highrisk MF (U.S. Food and Drug Administration [FDA]) or MF with disease-associated splenomegaly or symptoms (European Medicines Agency [EMA]) and remains the standard of care. However, although 2 phase 3 clinical trials, COMFORT-I and -II, demonstrated that ruxolitinib induces rapid spleen volume reductions (SVR) as well as symptom improvement, treatment discontinuations are frequent (up to 60% in 3 y), 4 because of grade of ≥3 cytopenia, and resulting in suboptimal symptom control, risk of disease relapse, and decreased survival. [5][6][7] Nearly a decade later, the selective JAK2 and FMS-like tyrosine kinase 3 (FLT3) inhibitor fedratinib was approved for the treatment of intermediate and high-risk MF (FDA) or MF with disease-associated splenomegaly or symptoms (EMA). Although

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

“…Ruxolitinib has been proven not only to alleviate the symptoms, and effectively reduce spleen size, but also to lower the level of blood cytokines, and possibly increase the overall survival although the conclusion remains controversial [120,121]. Three additional small-molecule kinase inhibitors have been approved by the United States Food and Drug Administration (US FDA) for the treatment of MF [122,123] (Table 3). JAK inhibitors are not mutationspecific; therefore, JAK2 mutations are not a required selection criterion for treatment.…”